This application presents a new concept of a unique genetic complex which appears to be of great biological significance since it controls host resistance, in the mouse, to at least three, but most likely to a variety of intracellular pathogens. This gene complex is located on the 1st chromosome and it is the primary regulator of resistance to Salmonella typhimurium, Leishmania donovani, and, as recently discovered in our laboratory, to Mycobacterium bovis, BCG. In all three instances the resistant allele expresses itself as a decreased multiplication index in vivo (slow or null net growth rate) of the particular infectious agent. This is demonstrable, in each case, very early in the course of infection, prior to the onset of specific immune respones; thus, the proposed designation of the complex: INR (for "innate resistance"). This complex provides a new, powerful tool for the study of the mechanisms of host-parasite relationship in infections with intracellular pathogens. Specific aims of the research proposed in this application are: (1) To formally establish the existence of INR gene complex. (2) To crease congenic lines of mice which will be identical except for the presence of either the resistant or the sensitive allele of the INR gene. (3) To define the cellular basis of the phenotypic expression of INR gene complex. (4) To analyze the development of acquired resistance (specific immunity) to each of the microorganisms under consideration in relation to the particular INR phenotype. Long-term objectives of this proposal are (a) to identify the INR-gene product and to define its mode of action, (b) to develop a typing method, independent of destructive infection, for the presence of the sensitive or resistant allele of the INR gene, (c) to develop a strategy of protection and therapy of the genetically sensitive host. Significance. Understanding of the mechanisms regulated by the INR gene complex and of their interaction with acquired immune processes will lead to more successful manipulation of anti-microbial defenses in favour of the host. This is of particular importance in the case of chronic infections with intracellular parasites which still constitute a major, world-wide health problem.